Insulin response to glucose is reduced in overt as well as chemical diabetes, but also in some healthy subjects (low insulin responders). A prospective study is planned in which subjects selected according to insulin response and sensitivity to insulin will be followed. Results of glucose infusion tests will be evaluated by mathematical modelling. The future occurrence of diabetes and vasculopathy will be related to insulin response, ethnic group, socio-economic characteristics. In a parallel study, Acomys cahirinus, a rodent with low insulin response and liability to develop diabetes, will be individually characterized as to insulin release and insulin sensitivity, the genetics of these tested, and animals observed for later appearance of diabetes. The role of cAMP for insulin release will be investigated in islets of rat, Acomys and diabetic Chinese hamster by adenine prelabeling method. The effect of insulin releasers (glucose, sulfonylureas) and non-releasers (cholera toxin) will be tested under various conditions, including low temperature and response of D2O, in order to dissociate cAMP and insulin responses and thus define their requirements and interrelations. Time-bound, glucose-incuded potentiation of insulin release will be investigated in normal and diabetic man; pancreas perfusion and islet perifusion will be used for characterizing its kinetics and mechanisms in states with normal and decreased insulin response. Since this glucose function is intact in diabetic man, means of enforcing potentiation and thus ameliorating insulin release will be investigated. The possibility that time-dependent effects apply also to glucagon release will be tested in the perfused pancreas by sequential stimulations (arginine) and inhibitions (glucose). In low insulin responders and diabetics, the dose-kinetics of glucose suppression of glucagon response to arginine will be tested to establish when and how this effect disappears in diabetes. The mechanism for the increased hepatic sensitivity to insulin of low responders will be investigated using perifused liver fragments from Acomys, with the hope to develop methods for increasing the insulin effect in diabetic livers.